Substituted 6,7-dihydro-5H-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof

Abstract

Compounds of formula (I): ##STR00001##
wherein R1 and R2 represent hydrogen or deuterium atoms; R3 represents a hydrogen atom or a COOH, a OH or a OPO(OH).sub.2 group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a hydrogen atom or a OH group; wherein at least one of R3 or R5 is different from a hydrogen atom; when R3 represents a COOH, OH or OPO(OH).sub.2 group, then R5 represents a hydrogen atom; when R5 represents a OH group, then R3 and R4 represent hydrogen atoms; and R6 is selected from an optionally substituted phenyl, heteroaryl, cycloalkyl and heterocycloalkyl group;
and the preparation and the therapeutic uses of the compounds of formula (I) as inhibitors and degraders of estrogen receptors, useful especially in the treatment of cancer.

Claims

1. A method of treating a disease involving inhibition and degradation of estrogen receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): ##STR00343## wherein: R1 and R2 represent independently a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a COOH group, a OH group, or a OPO(OH).sub.2 group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a hydrogen atom or a OH group; wherein: at least one of R3 or R5 is different from a hydrogen atom; when R3 represents a COOH group, a OH group or a OPO(OH).sub.2 group, then R5 represents a hydrogen atom; and when R5 represents a OH group, then R3 and R4 represent hydrogen atoms; R6 is selected from the group consisting of a phenyl group or a heteroaryl group comprising 3 to 9 carbon atoms and comprising from 1 to 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur, said phenyl and heteroaryl groups being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a (C.sub.1-C.sub.6)-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; a OH group; a (C.sub.1-C.sub.6)-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C.sub.1-C.sub.6)-alkyl groups substituted with two or more fluorine atoms; a sulfonyl-(C.sub.1-C.sub.6)-alkyl group wherein said (C.sub.1-C.sub.6)-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with 3 (C.sub.1-C.sub.6)-alkyl groups; an amine group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; an amide group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur; and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group; and a cycloalkyl group or a heterocycloalkyl group comprising 4 to 9 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur, said cycloalkyl or heterocycloalkyl groups being saturated or partially saturated and being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a fluorine atom; a OH group; a (C.sub.1-C.sub.6)-alkyl group; a COOR7 group wherein R7 is an (C.sub.1-C.sub.6)-alkyl group; and an oxo group; or a pharmaceutically acceptable salt thereof; wherein said disease is selected from the group consisting of ovulatory dysfunction, endometriosis, osteoporosis, benign prostatic hypertrophy, inflammation, and an estrogen receptor dependent cancer selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, uterine cancer, cervical cancer, and metastasis of said estrogen receptor dependent cancer.

2. A method of treating ovulatory dysfunction, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of ##STR00344## formula (I): wherein: R1 and R2 represent independently a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a COOH group, a OH group, or a OPO(OH).sub.2 group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a hydrogen atom or a OH group; wherein: at least one of R3 or R5 is different from a hydrogen atom; when R3 represents a COOH group, a OH group or a OPO(OH).sub.2 group, then R5 represents a hydrogen atom; and when R5 represents a OH group, then R3 and R4 represent hydrogen atoms; R6 is selected from the group consisting of a phenyl group or a heteroaryl group comprising 3 to 9 carbon atoms and comprising from 1 to 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur, said phenyl and heteroaryl groups being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a (C.sub.1-C.sub.6)-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; a OH group; a (C.sub.1-C.sub.6)-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C.sub.1-C.sub.6)-alkyl groups substituted with two or more fluorine atoms; a sulfonyl-(C.sub.1-C.sub.6)-alkyl group wherein said (C.sub.1-C.sub.6)-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with 3 (C.sub.1-C.sub.6)-alkyl groups; an amine group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; an amide group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur; and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group; and a cycloalkyl group or a heterocycloalkyl group comprising 4 to 9 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur, said cycloalkyl or heterocycloalkyl groups being saturated or partially saturated and being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a fluorine atom; a OH group; a (C.sub.1-C.sub.6)-alkyl group; a COOR7 group wherein R7 is an (C.sub.1-C.sub.6)-alkyl group; and an oxo group, or a pharmaceutically acceptable salt thereof.

3. A method of treating an estrogen receptor dependent cancer selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, uterine cancer, cervical cancer, and metastasis of said estrogen receptor dependent cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): ##STR00345## wherein: R1 and R2 represent independently a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a COOH group, a OH group, or a OPO(OH).sub.2 group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a hydrogen atom or a OH group; wherein: at least one of R3 or R5 is different from a hydrogen atom; when R3 represents a COOH group, a OH group or a OPO(OH).sub.2 group, then R5 represents a hydrogen atom; and when R5 represents a OH group, then R3 and R4 represent hydrogen atoms; R6 is selected from the group consisting of a phenyl group or a heteroaryl group comprising 3 to 9 carbon atoms and comprising from 1 to 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur, said phenyl and heteroaryl groups being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a (C.sub.1-C.sub.6)-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; a OH group; a (C.sub.1-C.sub.6)-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C.sub.1-C.sub.6)-alkyl groups substituted with two or more fluorine atoms; a sulfonyl-(C.sub.1-C.sub.6)-alkyl group wherein said (C.sub.1-C.sub.6)-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with 3 (C.sub.1-C.sub.6)-alkyl groups; an amine group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; an amide group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur; and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group; and a cycloalkyl group or a heterocycloalkyl group comprising 4 to 9 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur, said cycloalkyl or heterocycloalkyl groups being saturated or partially saturated and being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a fluorine atom; a OH group; a (C.sub.1-C.sub.6)-alkyl group; a COOR7 group wherein R7 is an (C.sub.1-C.sub.6)-alkyl group; and an oxo group, or a pharmaceutically acceptable salt thereof.

4. The method according to claim 3, wherein the metastasis is a cerebral metastasis.

5. The method according to claim 3, wherein the estrogen receptor dependent cancer is resistant to anti-hormonal treatment.

6. The method according to claim 2, wherein for the compound of formula (I), R6 is a phenyl group unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a (C.sub.1-C.sub.6)-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; a OH group; a (C.sub.1-C.sub.6)-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C.sub.1-C.sub.6)-alkyl groups substituted with two or more fluorine atoms; a sulfonyl-(C.sub.1-C.sub.6)-alkyl group wherein said (C.sub.1-C.sub.6)-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with 3 (C.sub.1-C.sub.6)-alkyl groups; an amine group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; an amide group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur; and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group; or a pharmaceutically acceptable salt thereof.

7. The method according to claim 2, wherein for the compound of formula (I), R6 is a phenyl group unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a methyl group; an ethyl group; an isopropyl group; a tert-butyl group; a CHF.sub.2 group; a CF.sub.3 group; a CF.sub.2CH.sub.3 group; a chlorine atom; a fluorine atom; a OH group; a OCH.sub.3 group; a OCH.sub.2CH.sub.3 group; a OCH.sub.2CH.sub.2F group; a OCHF.sub.2 group; a OCH.sub.2CF.sub.2 group; a OCF.sub.3 group; a OCH.sub.2CF.sub.3 group; a cyano group; a SCHF.sub.2 group; a SCF.sub.3 group; a SF.sub.5 group; a SO.sub.2CH.sub.3 group; a SO.sub.2CF.sub.3 group; a Si(CH.sub.3).sub.3 group; an oxetane group; a piperidine group; a morpholine group; a pyrrolidine group; and a triazolone group; or a pharmaceutically acceptable salt thereof.

8. The method according to claim 2, wherein for the compound of formula (I), R3 is a COOH group or a OH group; or a pharmaceutically acceptable salt thereof.

9. The method according to claim 3, wherein for the compound of formula (I), R6 is a phenyl group unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a (C.sub.1-C.sub.6)-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; a OH group; a (C.sub.1-C.sub.6)-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C.sub.1-C.sub.6)-alkyl groups substituted with two or more fluorine atoms; a sulfonyl-(C.sub.1-C.sub.6)-alkyl group wherein said (C.sub.1-C.sub.6)-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with 3 (C.sub.1-C.sub.6)-alkyl groups; an amine group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; an amide group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur; and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group; or a pharmaceutically acceptable salt thereof.

10. The method according to claim 3, wherein for the compound of formula (I), R6 is a phenyl group unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a methyl group; an ethyl group; an isopropyl group; a tert-butyl group; a CHF.sub.2 group; a CF.sub.3 group; a CF.sub.2CH.sub.3 group; a chlorine atom; a fluorine atom; a OH group; a OCH.sub.3 group; a OCH.sub.2CH.sub.3 group; a OCH.sub.2CH.sub.2F group; a OCHF.sub.2 group; a OCH.sub.2CF.sub.2 group; a OCF.sub.3 group; a OCH.sub.2CF.sub.3 group; a cyano group; a SCHF.sub.2 group; a SCF.sub.3 group; a SF.sub.5 group; a SO.sub.2CH.sub.3 group; a SO.sub.2CF.sub.3 group; a Si(CH.sub.3).sub.3 group; an oxetane group; a piperidine group; a morpholine group; a pyrrolidine group; and a triazolone group; or a pharmaceutically acceptable salt thereof.

11. The method according to claim 3, wherein for the compound of formula (I), R3 is a COOH group or a OH group; or a pharmaceutically acceptable salt thereof.

12. The method according to claim 3, wherein the compound of formula (I) is 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-ol; or a pharmaceutically acceptale salt thereof.

13. The method according to claim 3, wherein the compound of formula (I) is 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid; or a pharmaceutically acceptale salt thereof.

14. The method according to claim 3, wherein the compound of formula (I) is 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptale salt thereof.

15. The method according to claim 3, wherein the compound of formula (I) is 6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptale salt thereof.

16. The method according to claim 3, wherein the compound of formula (I) is 6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptale salt thereof.

17. The method according to claim 3, wherein the compound of formula (I) is [5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl] dihydrogen phosphate; or a pharmaceutically acceptale salt thereof.

18. The method according to claim 3, wherein the estrogen receptor dependent cancer is breast cancer or a metastasis thereof.

19. The method according to claim 18, wherein the compound of formula (I) is 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-ol; or a pharmaceutically acceptale salt thereof.

20. The method according to claim 18, wherein the compound of formula (I) is 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid; or a pharmaceutically acceptale salt thereof.

21. The method according to claim 18, wherein the compound of formula (I) is 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptale salt thereof.

22. The method according to claim 18, wherein the compound of formula (I) is 6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptale salt thereof.

23. The method according to claim 18, wherein the compound of formula (I) is 6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptale salt thereof.

24. The method according to claim 18, wherein the compound of formula (I) is [5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl] dihydrogen phosphate; or a pharmaceutically acceptale salt thereof.

Description

EXAMPLES

Example 1

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-3-ol

(1) ##STR00289##
Method A:

(2) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-ol (D2) (80 mg, 173.8 mol) in dioxane/water (80/20; V/V; 4 ml), were added 4-hydroxyphenyl-boronic acid (23.97 mg, 173.77 mol), Cs.sub.2CO.sub.3 (119.02 mg, 364.92 mol), and Pd(dppf)Cl.sub.2 (8.51 mg, 10.43 mol). The reaction mixture was microwaved at 90 C. for 30 minutes, and purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 58 mg (71%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-3-ol.

Example 3

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-ol

(3) ##STR00290##

(4) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-ol (D2) (80 mg, 173.8 mol) in dioxane/water (80/20; V/V; 4 ml), were added 5-indolylboronic acid (30.77 mg, 191.15 mol), Cs.sub.2CO.sub.3 (119.02 mg, 364.92 mol), and Pd(dppf)Cl.sub.2 (8.51 mg, 10.43 mol). The reaction mixture was microwaved at 90 C. for 30 minutes, and purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 12 mg (14%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-01.

Example 4

6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-3-ol

(5) ##STR00291##

(6) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-2-ol (D2) (80 mg, 173.8 mol) in dioxane/water (80/20; V/V; 4 ml), were added 2-chloro-4-fluorophenylboronic acid (23.10 mg, 132.50 mol), Cs.sub.2CO.sub.3 (119.02 mg, 364.92 mol), and Pd(dppf)Cl.sub.2 (8.51 mg, 10.43 mol). The reaction mixture was microwaved at 90 C. for 30 minutes, and purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 50 mg (74%) of 6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-3-ol.

Example 5

6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(7) ##STR00292##

(8) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (60 mg, 130.33 mol) in dioxane/water (80/20; V/V; 3 ml), were added 2-chloro-4-fluorophenylboronic acid (23.43 mg, 130.33 mol), Cs.sub.2CO.sub.3 (89.26 mg, 273.69 mol), and Pd(dppf)Cl.sub.2 (6.39 mg, 7.82 mol). The reaction mixture was microwaved at 90 C. for 1 hour and purified by column chromatography eluting with a gradient of methanol in dichloromethane (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 52 mg (78.2%) of 6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 9

6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(9) ##STR00293##

(10) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (60 mg, 130.33 mol) in dioxane/water (80/20; V/V; 3 ml), were added 2-fluoro-4-methylphenylboronic acid (22.99 mg, 143.36 mol), Cs.sub.2CO.sub.3 (89.26 mg, 273.69 mol), and Pd(dppf)Cl.sub.2 (6.39 mg, 7.82 mol). The reaction mixture was heated at 80 C. for 1 hour and purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 52 mg (82%) of 6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 11

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

(11) ##STR00294##

(12) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (60 mg, 130.33 mol), in dioxane/water (80/20; V/V; 3 ml), were added (4-hydroxyphenyl)boronic acid (17.98 mg, 130.33 mol), Cs.sub.2CO.sub.3 (89.26 mg, 273.69 mol), and Pd(dppf)Cl.sub.2 (6.39 mg, 7.82 mol). The reaction mixture was microwaved at 90 C. for 40 minutes and poured in water. The aqueous phase was washed with DCM/MeOH solution (95/5; V/V) and the organic extracts dried over MgSO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 52 mg (41%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 21

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-indolin-5-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol

(13) ##STR00295##

(14) To a solution of 8-bromo-9-(4-((3S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (50 mg, 108,61 mol), in dioxane/water (80/20; V/V; 3 ml), were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (26.62 mg, 108.61 mol), Cs.sub.2CO.sub.3 (74.39 mg, 228.07 mol), and Pd(dppf)Cl.sub.2 (5.32 mg, 6.52 mol).

(15) The reaction mixture was microwaved at 90 C. for 45 minutes and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give 32 mg (59%) of 5-[4-[(3S)-1-(3-fluoropropyl) pyrrolidin-3-yl]oxyphenyl]-6-indolin-5-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 25

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

(16) ##STR00296##

(17) To a solution of 8-bromo-9-(4-((3S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (139.3 mg, 302.58 mol), in dioxane (2 ml) and water (1 ml), was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (81.01 mg, 363.09 mol), Cs.sub.2CO.sub.3 (197.17 mg, 605.15 mol), and Pd(dppf)Cl.sub.2 (13.28 mg, 18.15 mol). The reaction mixture was heated at 82 C. for 1.5 hours and partitioned between water and DCM. The aqueous phase was washed with DCM and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 63.7 mg (44.2%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 26

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

(18) ##STR00297##

(19) To a solution of 4-(5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Example 24, 78.2 mg, 138.97 mol), in MeOH (1.5 ml) was added HCl (120 l, 4N dioxane solution). The reaction mixture was stirred at room temperature for 2.5 hours and concentrated under reduced pressure. The residue was purified by strong cation exchange (SCX) column to give 60.9 mg (94.7%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1,2,3,6-tetrahydropyddin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 29

6-(2-fluoro-4-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(20) ##STR00298##

(21) To a solution of 8-bromo-9-(4-((3S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (125.5 mg, 272.60 mol), in dioxane (2 ml) and water (1 ml), were added 2-fluoro-4-methoxyphenylboronic acid (66.73 mg, 384.80 mol), Cs.sub.2CO.sub.3 (177.64 mg, 545.20 mol), and Pd(dppf)Cl.sub.2 (11.97 mg, 16.36 mol). The reaction mixture was heated at 90 C. for 1 hour and partitioned between water and DCM. The aqueous phase was washed with DCM and the organic phase concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in diisopropyl ether (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 78 mg (56.6%) of 6-(2-fluoro-4-methoxy-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 36

5-[4-[(3S)-1-(1,1-dideuterio-3-fluoro-propyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-fluoro-4-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

Step 1. Tert-butyl (3S)-3-(4-{3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate (E1)

(22) ##STR00299##

(23) To a solution of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (B2) (6.56 g, 16.72 mmol) in dioxane (45 ml), was added tert-butyl (3S)-3-[4-(4,4,5,5-tetrametramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1-carboxylate (c) (6.51 g, 16.72 mmol), Cs.sub.2CO.sub.3 (23 ml, 34.50 mmol), and Pd(dppf)Cl.sub.2 (1.44 g, 1.67 mmol). The reaction mixture was stirred at room temperature for 24 hours, and partitioned between water and AcOEt. The aqueous phase was extracted with AcOEt and the organic phase dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a mixture of heptane and DCM (60/40; V/V) to give 7.188 g (85%) of tert-butyl (3S)-3-(4-{3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate (E1).

(24) LC/MS (m/z, MH+): 507

Step 2. Tert-butyl (3S)-3-(4-{8-bromo-3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate (F1)

(25) ##STR00300##

(26) To a solution of tert-butyl (3S)-3(4-{3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate (E1) (7.18 g, 14.20 mmol) in THF (60 ml), was added pyridinium tribromide (5.00 g, 15.62 mmol). The reaction mixture was stirred at room temperature for 1 hour, and partitioned between water and AcOEt. The aqueous phase was extracted with AcOEt and the organic phase dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a mixture of DCM and MeOH (96/4; V/V) to give 3.43 g (41.3%) of tert-butyl (3S)-3-(4-{8-bromo-3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate (F1).

(27) LC/MS (m/z, MH+): 484 and 486 (M-BOC).

Step 3. Tert-butyl (3S)-3-(4-{3-[(2,2-dimethylpropanoyl)oxy]-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate (G1)

(28) ##STR00301##

(29) To a solution of (3S)-3-(4-{8-bromo-3-[(2,2-dimethylpropanoyl)oxy]-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate (F1) (500 mg, 855.37 mol) in dioxane (5 ml), was added 2-fluoro-4-methylphenylboronic acid (150.89 mg, 940.91 mol), Cs.sub.2CO.sub.3 (2.5 ml, 3.75 mmol), and Pd(dppf)Cl.sub.2 (65.88 mg, 85.54 mol). The reaction mixture was heated at 80 C. for 2 hours, and partitioned between water and AcOEt. The aqueous phase was extracted with AcOEt and the organic phase dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a mixture of heptane and DCM (50/50; V/V) to give 285 mg (54.3%) of tert-butyl (3S)-3-(4-{3-[(2,2-dimethylpropanoyl)oxy]-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl}phenoxy)pyrrolidine-1-carboxylate (G1).

(30) LC/MS (m/z, MH+): 614

Step 4. 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate hydrochloride salt (H1)

(31) ##STR00302##

(32) To a solution of tert-butyl (3S)-3-(4-{3-[(2,2-dimethylpropanoyl)oxy]-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl})phenoxy)pyrrolidine-1-carboxylate (G1) (295 mg, 480.65 mol) in MeOH (5 ml), was added hydrochloric acid in (4N, 1.20 ml, 4.80 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give a solid which was triturated with diisopropyl ether, filtered and dried to give 221 mg (59.5%) of 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate, as an hydrochloride salt (H1).

(33) LC/MS (m/z, MH+): 514

Step 5. 8-(2-Fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate (J1)

(34) ##STR00303##

(35) To a solution of 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (H1) (163 mg, 317.34 mol) in DMF (3 ml), was added 3-fluoropropanoic acid (30.76 mg, 317.34 mol), 4-dimethylaminopyridine (121.15 mg, 952.02 mol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (76.84 mg, 380.81 mol). The reaction mixture was stirred at room temperature for 2 hours, and partitioned between water and AcOEt. The aqueous phase was extracted with AcOEt and the organic phase dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a mixture of DCM and MeOH (97/3; V/V) to give 180 mg (96.5%) of 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate (J1).

(36) LC/MS (m/z, MH+): 588

Step 6. 5-[4-[(3S)-1-(1,1-dideuterio-3-fluoro-propyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-fluoro-4-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol (Ic)

(37) ##STR00304##

(38) To a solution of 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate (J1) (180 mg, 306.28 mol) in diethylether (5 ml), was added lithium aluminum deuteride (39.36 mg, 918.84 mol). The reaction mixture was stirred at room temperature for 2 hours, diluted with DCM and a solution of sodium potassium bis-tartrate (1N) was added. The solid formed was filtered and the filtrate was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a mixture of DCM and MeOH (97/3; V/V) to give 36 mg (23.9%) of 5-[4-[(3S)-1-(1,1-dideuterio-3-fluoro-propyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-fluoro-4-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol (Ic).

Example 39

6-(3-chloro-2-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

Step 1: 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D)

(39) ##STR00305##

(40) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (2.03 g, 4.41 mmol), in dioxane (25 ml) and water (10 ml), was added 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (1.34 g, 5.29 mmol), Cs.sub.2CO.sub.3 (2.88 g, 8.82 mmol), and Pd(dppf)Cl.sub.2 (203.77 mg, 264.56 mol). The reaction mixture was heated at 70 C. for 45 minutes, and partitioned between DCM and water. The phases were separated and the organic phase concentrated under reduced pressure. The residue was first purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a crude solid, which was further separated on chiralpak AD 20 m, eluting with a mixture of heptane, ethanol and triethylamine (90/9.9/0.1; V/V/V) to give 967 mg (43%) of 5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-8,9-dihydro-7H-benzocyclohepten-2-ol (D).

(41) LC/MS (m/z, MH.sup.+): 509

Step 2: 6-(3-chloro-2-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(42) ##STR00306##

(43) To a solution of 5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-8,9-dihydro-7H-benzocyclohepten-2-ol (D) (100.3 mg, 197.66 mol), in dioxane (1 ml) and water (0.5 ml), was added 3-chloro-2-fluoroiodobenzene (60.83 mg, 237.19 mol), Cs.sub.2CO.sub.3 (128.93 mg, 395.31 mol) and Pd(dppf)Cl.sub.2 (9.68 mg, 11.86 mol). The reaction mixture was heated at 70 C. for 6 hours, and partitioned between DCM and water. The aqueous phase was washed with DCM and organic phases were dried and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 18 mg (18%) of 6-(3-chloro-2-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 45

1-fluoro-6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(44) ##STR00307##

(45) To a solution of 8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D7) (60 mg, 125.43 mol), in dioxane (1 ml) and water (0.5 ml), was added 2-fluoro-4-methylphenylboronic acid (22.12 mg, 137.97 mol), Cs.sub.2CO.sub.3 (81.73 mg, 250.85 mol), and Pd(dppf)Cl.sub.2 (6.15 mg, 7.53 mol). The reaction mixture was heated at 80 C. for 30 minutes and the solid formed, filtered and washed with dioxane. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give 45 mg (71%) of 1-fluoro-6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 48

6-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

(46) Method C

Step 1. 8-(2-Fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate

(47) ##STR00308##

(48) To a solution of 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Example 9, 840 mg, 1.60 mmol), in DCM (30 ml), was added pyridine (387.4 l, 4.79 mmol), and trifluoromethanesulfonic anhydride (839.5 l, 4.79 mmol). The reaction mixture was stirred at room temperature for 16 hours, poured onto ice and partitioned between water and DCM. The aqueous phase was washed with DCM and the gathered organic phases, washed successively with a saturated solution of NaHCO.sub.3, and brine. The organic phase was dried over MgSO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to give 860 mg (86.6%) of crude 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate.

(49) LC/MS (m/z, MH.sup.+): 622

Step 2. Methyl 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

(50) ##STR00309##

(51) To a solution of 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (860 mg, 1.35 mmol), in DMF (10 ml) and MeOH (5 ml), was added triethylamine (1 ml), Pd(OAc).sub.2 (60.52 mg, 269.54 mol), and 1,3-bis(diphenylphosphino)propane (dppp) (115.80 mg, 269.54 mol). The reaction mixture was heated at 40 C., under an atmosphere of CO (2 bars), for 16 hours, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of cyclohexane and AcOEt (80/20; V/V) to give 400 mg (55.8%) of methyl 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

(52) LC/MS (m/z, MH.sup.+): 532

Step 3. 8-(2-Fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

(53) ##STR00310##

(54) To a solution of methyl 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (390 mg, 733.59 mol), MeOH (20 ml), was added NaOH solution (5N, 1.5 ml). The reaction mixture was heated at 60 C., for 2 hours, and concentrated under reduced pressure. The residue was taken up into water (25 ml), and acidified with aqueous HCl (5N, 1.5 ml), and the solid formed was filtered, washed with water and dried under vacuum. The residue was purified by trituration in diisopropyl ether to give 180 mg (47.4%) of 8-(2-fluoro-4-methylphenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Example 51

6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

(55) Method B

Step 1: 6-(2,4-Dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester

(56) ##STR00311##

(57) To a solution of methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (D5) (150 mg, 298.56 mol), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 mol), Cs.sub.2CO.sub.3 (204.48 mg, 626.97 mol), and Pd(dppf)Cl.sub.2 (14.63 mg, 17.91 mol). The reaction mixture was heated at 90 C. for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycoheptene-2-arboxylic acid methyl ester.

(58) LC/MS (m/z, MH.sup.+): 568

Step 2: 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

(59) ##STR00312##

(60) To a solution of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (80 mg, 140.72 mol) in MeOH (5 ml) was added a solution of NaOH (562.88 l, 5 M) and the reaction mixture was heated at 60 C. for 5 hours and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCl (5 M) added to pH 7. The slurry was extracted with DCM, dried over MgSO.sub.4 and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrle and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.

Example 63

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxy-2-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid hydrochloride

Step 1: 6-(4-Methoxy-2-methyl-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester

(61) ##STR00313##

(62) To a solution of methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy)phenyl}-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (D5) (250 mg, 497.60 mol), in dioxane (12 ml) and water (2 ml), was added 4-methoxy-2-methylphenyl-boronic acid (90.85 mg, 547.36 mol), Cs.sub.2CO.sub.3 (340.81 mg, 1.04 mmol), and Pd(dppf)Cl.sub.2 (24.38 mg, 29.86 mol). The reaction mixture was heated at 90 C. for 2 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 280 mg (100%) of crude 6-(4-methoxy-2-methyl-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.

(63) LC/MS (m/z, MH.sup.+): 544

Step 2: 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxy-2-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid hydrochloride

(64) ##STR00314##

(65) To a solution of 6-(4-methoxy-2-methyl-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (280 mg, 543.668 mol) in MeOH (10 ml) was added a solution of NaOH (5 M, 1.5 ml) and the reaction mixture was heated at 60 C. for 6 hours and the solvent removed under reduced pressure. The residue was taken up in water (25 ml) and aqueous HCl (5 M) was added to pH 7. The slurry was extracted with DCM, dried over MgSO.sub.4 and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give a solid. This solid was triturated in diisopropyl ether with anhydrous HCl (2 M in diethyl ether) to give a solid which was filtered and dried to give 134 mg (46%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxy-2-methyl-phenyl)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid hydrochloride.

Example 70

6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

Step 1: 1-[5-(5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-2,2-dimethyl-2,3-dihydro-indol-1-yl]-ethanone

(66) ##STR00315##

(67) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (93.8 mg, 203.75 mol), in dioxane (1 ml) and water (0.5 ml), was added 1-(2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)ethanone (64.72 mg, 205.32 mol), Cs.sub.2CO.sub.3 (132.90 mg, 407.49 mol), and Pd(dppf)Cl.sub.2 (9.98 mg, 12.22 mol). The reaction mixture was heated at 72 C. for 45 minutes, and partitioned between DCM and water. The phases were separated on hydrophobic interaction column and the organic phase concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 77 mg (67%) of 1-[5-(5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-2,2-dimethyl-2,3-dihydro-indol-1-yl]-ethanone.

(68) LC/MS (m/z, MH.sup.+): 569

Step 2: 6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(69) ##STR00316##

(70) To a solution of (S)-1-(5-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-8-yl)-2,2-dimethylindolin-1-yl)ethanone (73 mg, 128.36 mol) in dioxane (1.9 ml), was added aqueous HCl (1N, 1.5 ml) and the reaction mixture heated in a microwave oven at 120 C. for 2 hours. The reaction mixture was poured onto a saturated aqueous solution of NaHCO.sub.3, and extracted with DCM. The phases were separated on hydrophobic interaction column and the organic phase concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give 39 mg (58%) of 6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 73

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1,2,3,4-tetrahydroquinolin-6-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

Step 1: 6-(5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester

(71) ##STR00317##

(72) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (93.4 mg, 202.88 mol), in dioxane (1 ml) and water (0.5 ml), was added tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1 (2H)-carboxylate (85.18 mg, 237.09 mol), Cs.sub.2CO.sub.3 (132.33 mg, 405.75 mol), and Pd(dppf)Cl.sub.2(9 9.94 mg, 12.17 mol). The reaction mixture was heated at 72 C. for 45 minutes, and partitioned between DCM and water. The phases were separated on hydrophobic interaction column and the organic phase concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give 75 mg (60.3%) of 6-(5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester.

(73) LC/MS (m/z, MH.sup.+): 613

Step 2: 6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(74) ##STR00318##

(75) To a solution of 6-(5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester in DCM (2.4 ml) was added HCl (1M in diethylether, 1.17 ml) and the reaction mixture stirred at room temperature for 18 hours. A saturated aqueous NaHCO.sub.3 solution was added, and the aqueous phase was extracted with DCM. The phases were separated on hydrophobic interaction column and the organic phase concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give 57.3 mg (95.1%) of 6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 75

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(76) ##STR00319##

(77) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (92.9 mg, 201.79 mol), in dioxane (1 ml) and water (0.5 ml), was added 4-(trifluoromethoxy)phenylboronic acid (54.12 mg, 254.93 mol), Cs.sub.2CO.sub.3 (131.63 mg, 403.58 mol), and Pd(dppf)Cl.sub.2 (9.89 mg, 12.11 mol). The reaction mixture was heated at 72 C. for 45 minutes, and partitioned between DCM and water. The phases were separated on hydrophobic interaction column and the organic phase concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give 71.3 mg (61.4%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 76

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

(78) ##STR00320##

(79) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (74.9 mg, 162.69 mol), in dioxane (1 ml) and water (0.5 ml), was added 4-methoxyphenylboronic acid (34.49 mg, 222.45 mol), Cs.sub.2CO.sub.3 (131.91 mg, 404.45 mol), and Pd(dppf)Cl.sub.2 (9.91 mg, 12.13 mol). The reaction mixture was heated at 72 C. for 45 minutes, and partitioned between DCM and water. The phases were separated on hydrophobic interaction column and the organic phase concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 63.9 mg (64.8%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-methoxyphenyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 82

6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl) pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(80) ##STR00321##

(81) To a solution of 8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D7) (60 mg, 125.43 mol), in dioxane (1 ml) and water (0.5 ml), was added 6-ethoxy-2-fluoropyndin-3-yl boronic acid (25.52 mg, 137.97 mol), Cs.sub.2CO.sub.3 (171.05 mg, 525.0 mol), and Pd(dppf)Cl.sub.2 (9.66 mg, 12.54 mol). The reaction mixture was heated at 60 C. for 1 hour and partitioned between water and AcOEt. The aqueous phase was washed with AcOEt and the organic extracts dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified twice by column chromatography eluting first with a mixture of diisopropyl ether/MeOH (90/10; V/V) and with a mixture of DCM/MeOH (98/2) to give 38 mg (56.3%) of 6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 107

6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(82) ##STR00322##

(83) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (74.9 mg, 162.69 mol), in dioxane (1 ml) and water (0.5 ml), was added 2-ethoxypyrimidin-5-yl boronic acid (30.06 mg, 178.96 mol), Cs.sub.2CO.sub.3 (106.12 mg, 325.38 mol), and Pd(dppf)Cl.sub.2 (7.97 mg, 9.76 mol). The reaction mixture was heated at 72 C. for 1 hour, partitioned between water and DCM and phases separated on hydrophobic partition column. The organic solvents were concentrated under reduced pressure and the residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 47.3 mg (57.7%) of 6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-01.

Example 108

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(6-methoxy-3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

(84) ##STR00323##

(85) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (90 mg, 195,49 mol), in dioxane/water (80/20; V/V; 4 ml), was added 2-methoxy-5-pyridineboronic acid (37.77 mg, 234.59 mol), Cs.sub.2CO.sub.3 (133.89 mg, 410.53 mol), and Pd(dppf)Cl.sub.2 (9.58 mg, 11.73 mol). The reaction mixture was heated in a microwave at 90 C. for 30 minutes, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 4%) to give a solid which was further purified on strong cation exchange (SCX) column to give 59 mg (61.8%) of 5-[4-[(3S)-1-(3-fluoropropyl) pyrrolidin-3-yl]oxyphenyl]-6-(6-methoxy-3-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 109

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(2-methoxy-4-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

(86) ##STR00324##

(87) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (90 mg, 195.49 mol), in dioxane/water (80/20; V/V; 4 ml), was added 2-methoxypyridine-4-boronic acid (36.99 mg, 234.59 mol), Cs.sub.2CO.sub.3 (133.89 mg, 410.53 mol), and Pd(dppf)Cl.sub.2 (9.58 mg, 11.73 mol). The reaction mixture was heated in a microwave at 90 C. for 30 minutes, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 4%) to give a solid which was further purified on strong cation exchange (SCX) column to give 60 mg (62.8%) of 5-[4-[(3S)-1-(3-fluoropropyl) pyrrolidin-3-yl]oxyphenyl]-6-(2-methoxy-4-pyridyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 114

1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(88) ##STR00325##

(89) To a solution of 8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D7) (60 mg, 125.43 mol), in dioxane (1 ml) and water (0.5 ml), was added 4-(trifluoromethoxy)phenylboronic acid (29 mg, 137.97 mol), Cs.sub.2CO.sub.3 (81.73 mg, 250.85 mol), and Pd(dppf)Cl.sub.2 (6.15 mg, 7.53 mol). The reaction mixture was heated at 80 C. for 30 minutes and the solid filtered and washed with dioxane.

(90) The filtrate was concentrated under educed pressure and the residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give 45 mg (71%) of 1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 163

[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl]dihydrogen phosphate

Step 1: Diethyl 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-benzo[7]annulen-3-yl phosphate

(91) ##STR00326##

(92) To a solution of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol (Example 75, 312 mg, 576.10 mol), in acetonitrle (3 ml), was added triethylamine (353.1 l, 2.54 mmol), and diethyl chlorophosphate (249.76 l, 1.73 mmol). The reaction mixture was stirred at room temperature for 28 hours, and concentrated under reduced pressure. The residue was purified by strong cation exchange (SCX) column to give 256 mg (65.6%) of diethyl 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-benzo[7]annulen-3-yl phosphate.

(93) LC/MS (m/z, MH.sup.+): 678

Step 2: [5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl]dihydrogen phosphate

(94) ##STR00327##

(95) To a solution of diethyl 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-benzo[7]annulen-3-yl phosphate (256 mg, 377.77 mol), in acetonitrile (6 ml), was added iodotrimethylsilane (277.12 l, 1.89 mmol). The reaction mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was purified by strong cation exchange (SCX) column and reverse phase column chromatography, eluting with a gradient of acetonitrile in water (20% to 80%) to give 167 mg (70.3%) of [5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl]dihydrogen phosphate.

Example 174

6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid hydrochloride

Step 1: Methyl 8-(2,2-dimethyl-2,3-dihydro-1H-indol-5-yl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

(96) ##STR00328##

(97) To a solution of methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (D5) (500 mg, 845.91 mol), in dioxane (12 ml) and water (2 ml), was added 1-(2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)ethanone (279.98 mg, 888.21 mol), Cs.sub.2CO.sub.3 (744.91 mg, 2.28 mmol), and Pd(dppf)Cl.sub.2 (41.45 mg, 50.75 mol). The reaction mixture was heated in a microwave at 110 C. for 1 hour, DCM was added and the organic phase washed with saturated NH.sub.4Cl solution. The organic phase was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 250 mg (48.4%) of methyl 8-(2,2-dimethyl-2,3-dihydro-1H-indol-5-yl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

(98) LC/MS (m/z, MH.sup.+): 611

Step 2: 6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid hydrochloride

(99) ##STR00329##

(100) To a solution of methyl 8-(2,2-dimethyl-2,3-dihydro-1H-indol-5-yl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (240 mg, 392.95 mol) in MeOH (20 ml) was added NaOH (15.72 mg, 392.95 mol) and the reaction mixture was heated under reflux for 3 hours and the solvent removed under reduced pressure. The residue was taken up in water (15 ml), HCl (5 M, 1 ml) was added and the reaction mixture was heated under reflux for 2 hours. NaOH solution was added to pH 7, and the aqueous phase extracted with DCM. The organic phase was washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried to give 211 mg (90.8%) of 6-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid hydrochloride.

Example 189

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-oxidopyndin-1-ium-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

Step 1: 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate

(101) ##STR00330##

(102) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D3) (1 g, 1.84 mmol), in dioxane (10 ml) and water (5 ml), was added 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (559.65 mg, 2.20 mmol), Cs.sub.2CO.sub.3 (1.20 g, 3.67 mmol), and Pd(dppf)Cl.sub.2 (84.87 mg, 110.19 mol). The reaction mixture was heated under reflux for 24 hours, and partitioned between DCM and water. The aqueous phase was washed with DCM and the gathered organic phase dried over hydrophobic partition column, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM and MeOH (98/2; V/V) to give 426 mg (39.2%) of 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate.

(103) LC/MS (m/z, MH+): 592 (M+H).

Step 2: [9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-8-yl]boronic acid

(104) ##STR00331##

(105) To a solution of 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate (426 mg, 720.13 mol), in MeOH (10 ml), was added NaOH (2N, 2.16 ml, 4.32 mmol). The reaction mixture was stirred at room temperature for 1.5 hour, and HCl (2N, 2.2 ml) was added. The aqueous phases was washed with DCM, and evaporated under reduced pressure. The residue was triturated with a mixture of DCM and MeOH (95/5, V/V), filtered and concentrated under reduced pressure to give 100 mg (32.7%) of crude [9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-8-yl]boronic acid.

(106) LC/MS (m/z, MH+): 426 (M+H).

Step 3: 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-oxidopyridin-1-ium-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

(107) ##STR00332##

(108) To a solution of [9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-8-yl]boronic acid (100 mg, 235.12 mol), in dioxane (8 ml) and water (2 ml), 4-bromopyridine 1-oxide (57.28 mg, 329.17 mol), Cs.sub.2CO.sub.3 (161.04 mg, 493.76 mol) and Pd(dppf)Cl.sub.2 (11.52 mg, 14.11 mol). The reaction mixture was heated at 90 C. for 2 hours, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 4%) to give a solid which was further purified on strong cation exchange (SCX) column to give 21 mg (18.8%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-oxidopyndin-1-ium-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 203

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-tetrahydropyran-4-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol

(109) ##STR00333##

(110) To a solution of 6-(3,6-dihydro-2H-pyran-4-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol (Example 202, 110 mg, 237.28 mol) in AcOEt (3 ml) and ethanol (5 ml), was added palladium on carbon (10%, 2.53 mg, 23.73 mol). The reaction mixture was stirred at 50 C. under hydrogen atmosphere (5 bars) for 2 hours. The reaction mixture was filtered on celite, washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM and MeOH (90/10; V/V)) to give 61 mg (55%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-tetrahydropyran-4-yl-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 204

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxycyclohexyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

Step 1: 6-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

(111) ##STR00334##

(112) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (500 mg, 1.09 mmol), in dioxane/water (80/20; V/V, 25 ml), was added 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacoyl ester (412.93 mg, 1.52 mmol), Cs.sub.2CO.sub.3 (743.85 mg, 2.28 mmol), and Pd(dppf)Cl.sub.2 (53.22 mg, 65.16 mol). The reaction mixture was heated at 80 C. for 30 minutes, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 4%) to give a solid which was further purified on strong cation exchange (SCX) column to give 485 mg (85.9%) of 6-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol.

(113) LC/MS (m/z, MH+): 520

Step 2: 6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

(114) ##STR00335##

(115) To a solution of 6-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol (485 mg, 933.31 mol), in AcOEt (10 ml) and ethanol (10 ml), was added palladium on carbon (10%, 9.93 mg, 93.33 mol). The reaction mixture was stirred at 50 C. under hydrogen atmosphere (5 bars) for 24 hours. The reaction mixture was filtered over celite, rinsed with MeOH and the filtrate was concentrated under reduced pressure to give 487 mg (100%) of crude 6-(1,4-dioxa-spiro[4.5]dec-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol.

(116) LC/MS (m/z, MH.sup.+): 522

Step 3: 4-(5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-cyclohexanone

(117) ##STR00336##

(118) To a solution of crude 6-(1,4-dioxa-spiro[4.5]dec-8-yl)-5-{4-[(S)-1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol (487 mg, 933.53 mol) in acetone (2 ml) was added concentrated aqueous HCl (1.4 ml) and the reaction mixture was stirred at room temperature for 4 days. A saturated aqueous solution of NaHCO.sub.3 and DCM was added and the phases were separated on hydrophobic interaction column. The organic phase was concentrated under reduced pressure and the residue purified by column chromatography eluting with a mixture of MeOH in DCM (3/97; V/V) to give 390 mg (87.5%) of 4-(5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-cyclohexanone.

(119) LC/MS (m/z, MH.sup.+): 478.

Step 4: 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxycyclohexyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

(120) ##STR00337##

(121) To a solution of 4-(5-{4-[(S)-1-(3-Fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-2-hydroxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-cyclohexanone (200 mg, 418,74 mol), in MeOH (4 ml), was added sodium borohydride (147.3 mg, 3.89 mmol). The reaction mixture was stirred at room temperature for 4 days, and water was added. A solid forms which was filtered, rinsed with water and purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give 28 mg (14%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxycyclohexyl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

Example 207

6-(4,4-difluorocyclohexen-1-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(122) ##STR00338##

(123) To a solution of 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (200 mg, 434,42 mol) in dioxane/water (80/20; V/V, 10 ml), was added 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (127.24 mg, 521.30 mol), Cs.sub.2CO.sub.3 (297.53 mg, 912.28 mol), and Pd(dppf)Cl.sub.2 (20.08 mg, 26.07 mol). The reaction mixture was heated at 90 C. for 30 minutes, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give a solid which was further purified on strong cation exchange (SCX) column to give 95 mg (44%) of 6-(4,4-difluorocyclohexen-1-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 208

6-(4,4-difluorocyclohexyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

(124) ##STR00339##

(125) To a solution of 6-(4,4-difluorocyclohexen-1-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol (95 mg, 190.92 mol), in AcOEt (3 ml) and ethanol (5 ml) was added palladium on carbon (10%, 2.03 mg, 19.09 mol). The reaction mixture was stirred at 50 C. under hydrogen atmosphere (5 bars) for 2 hours and filtered on celite, rinsed with MeOH and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of MeOH in DCM (3/97; V/V) to give 70 mg (73.4%) of 6-(4,4-difluorocyclohexyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 213

6-(2-chloro-4-fluoro-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

Step 1: Methyl 8-(2-chloro-4-fluorophenyl)-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

(126) ##STR00340##

(127) To a solution of methyl 8-bromo-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, hydrobromide (DS) (200 mg, 332.60 mol) in dioxane (15 ml) was added 2-chloro-4-fluorophenyl boronic acid (69.59 mg, 399.12 mol), Cs.sub.2CO.sub.3 (465.64 l, 698.46 mol), and Pd(dppf)Cl.sub.2 (15.37 mg, 19.96 mol). The reaction mixture was heated at 70 C. for 1 hour, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 5%), to give a solid which was further purified on strong cation exchange (SCX) column to give 170 mg (89.7%) of methyl 8-(2-chloro-4-fluorophenyl)-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

(128) LC/MS (m/z, MH.sup.+): 570

Step 2: 6-(2-chloro-4-fluoro-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

(129) ##STR00341##

(130) To a solution of methyl 8-(2-chloro-4-fluorophenyl)-4-fluoro-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (170 mg, 298.22 mol) in MeOH (150 ml), was added NaOH 5 M (238.58 l, 1.19 mmol). The reaction mixture was heated at 90 C. for 2 hours, aqueous HCl (5 N) was added, and purified on strong cation exchange (SCX) column to give 65 mg (39.2%) of 6-(2-chloro-4-fluoro-phenyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.

Example 215

5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol

(131) ##STR00342##

(132) To a solution of 8-bromo-9-(4-((3S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (306.6 mg, 665.97 mol), in dioxane (4 mL) and water (0.5 ml), was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (201 mg, 823.43 mol), Cs.sub.2CO.sub.3 (557 mg, 1.71 mmol), and Pd(dppf)Cl.sub.2 (70 mg, 85.72 mol). The reaction mixture was heated at 72 C. for 4 hours and partitioned between water and DCM. The phases were separated on hydrophobic interaction column and the organic phase concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to give 26 mg (8%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indazol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol.

(133) Some compounds of formula (I) were subjected to pharmacological tests for determining their antagonist and degradation effects on estrogen receptors.

(134) Test A: Biochemical Antagonist Activity on Wild Type (WT) and Mutants Estrogen Receptors

(135) Test A involves measuring the in vitro antagonist activity of a compound of formula (I) on estrogen receptors.

(136) The measurements of the antagonist activities were made using an estrogen receptor coactivator assay as described hereunder.

(137) Antagonistic potency of compounds was evaluated using LanthaScreen TR-FRET ER Coactivator Assay (ThermoFisher) with modifications. It is a competition assay, where binding of a test compound to a complex comprised of (i) His6-ER298-554 protein representing ER ligand-binding domain, (ii) Tb-labeled His6 antibody, (iii) a fluorescein-labeled PGC1a coactivator peptide (EAEEPSLLKKLLLAPANTQ), and (iv) estradiol, results in a decrease of the TR-FRET signal due to dissociation of the coactivator peptide. His6-ER298-554 proteins were expressed as WT or D538G or Y537S mutants in E. coli and purified by affinity chromatography. The assay works in a homogeneous mix-and-read format. In a typical experiment, a 4 L mixture of 0.5 nM His6-ER298-554, 0.5 nM Tb-labeled His6 antibody, 250 nM PGC1a peptide, and 3 nM estradiol in 100 mM potassium phosphate, pH 7.4, 0.01% Tween-20, 0.02% NaN.sub.3, 5 mM DTT, was added to 40 nL test compound in DMSO and incubated overnight at room temperature. The TR-FRET 520:495 nm emission ratio was calculated and used to determine the IC50 value from a dose response curve fit to the 4-parameter logistic equation.

(138) The antagonist activity with respect to estrogen receptors in this test is given by the concentration which inhibits 50% of the estrogen receptor activity (or IC50) in nM.

(139) The Table 2 below indicates the biochemical results of antagonist activity on WT and mutants estrogen receptors for compounds of formula (I), and demonstrates that the compounds tested have an antagonist activity regarding estrogen receptors.

(140) TABLE-US-00002 TABLE 2 Antagonism WT Antagonism D538G Antagonism Y537S Examples IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) Example 1 7 32 22 Example 2 5 30 22 Example 3 37 268 139 Example 4 19 117 68 Example 5 7 21 21 Example 6 2 4 3 Example 7 5 36 19 Example 8 3 15 8 Example 9 3 20 10 Example 10 2 5 3 Example 11 2 4 3 Example 12 3 18 10 Example 13 4 19 11 Example 14 3 15 7 Example 15 5 37 24 Example 16 14 109 63 Example 17 3 24 15 Example 18 5 28 21 Example 19 8 49 26 Example 20 2 12 9 Example 21 7 30 26 Example 22 7 45 26 Example 23 3 9 4 Example 24 152 759 475 Example 25 284 937 726 Example 26 199 443 341 Example 27 3 10 6 Example 28 2 5 4 Example 29 2 4 2 Example 30 5 20 9 Example 31 2 19 12 Example 32 3 32 24 Example 33 3 41 24 Example 34 2 18 11 Example 35 12 244 134 Example 36 3 90 50 Example 37 14 309 241 Example 38 39 652 651 Example 39 4 76 53 Example 40 16 289 224 Example 41 10 177 133 Example 42 2 55 33 Example 43 0.8 14 11 Example 44 1 16 12 Example 45 2 40 23 Example 46 1 21 16 Example 47 2 31 23 Example 48 44 1119 549 Example 49 1 11 6 Example 50 10 208 113 Example 51 15 389 221 Example 52 2 49 29 Example 53 244 3541 2857 Example 54 1 8 5 Example 55 23 635 338 Example 56 15 389 204 Example 57 3 56 39 Example 58 2 37 24 Example 59 2 57 34 Example 60 3 68 39 Example 61 10 178 99 Example 62 20 337 178 Example 63 6 132 72 Example 64 6 149 88 Example 65 2 38 25 Example 66 12 217 127 Example 67 5 145 85 Example 68 12 184 109 Example 69 5 172 90 Example 70 2 36 22 Example 71 1 28 18 Example 72 31 895 498 Example 73 4 59 40 Example 74 2 28 26 Example 75 56 1295 679 Example 76 2 40 23 Example 77 1 19 13 Example 78 17 298 185 Example 79 9 182 113 Example 80 13 389 203 Example 81 7 128 93 Example 82 1 24 16 Example 83 51 842 648 Example 84 74 1464 964 Example 85 58 1111 735 Example 86 12 313 172 Example 87 9 150 93 Example 88 5 139 78 Example 89 1 12 8 Example 90 13 263 190 Example 91 2 35 18 Example 92 34 840 504 Example 93 2 29 24 Example 94 25 485 322 Example 95 12 243 150 Example 96 20 307 196 Example 97 9 127 78 Example 98 1 18 12 Example 99 18 804 280 Example 100 83 1329 1014 Example 101 14 269 163 Example 102 5 123 71 Example 103 4 86 55 Example 104 2 30 17 Example 105 8 129 81 Example 106 15 524 607 Example 107 42 977 507 Example 108 1 33 19 Example 109 1 29 17 Example 110 14 274 168 Example 111 4 120 67 Example 112 4 76 46 Example 113 34 633 434 Example 114 21 346 242 Example 115 6 86 71 Example 116 2 37 25 Example 117 12 238 163 Example 118 17 245 164 Example 119 62 953 714 Example 120 38 585 357 Example 121 4 76 56 Example 122 2 40 24 Example 123 4 72 46 Example 124 13 215 170 Example 125 8 154 106 Example 126 33 661 541 Example 127 30 603 347 Example 128 89 2046 1692 Example 129 23 474 290 Example 130 3 59 44 Example 131 15 387 253 Example 132 77 1371 1249 Example 133 20 384 190 Example 134 2 28 28 Example 135 59 1077 1226 Example 136 11 201 134 Example 137 28 595 363 Example 138 50 697 323 Example 139 2 43 28 Example 140 52 996 685 Example 141 27 475 436 Example 142 5 117 64 Example 143 4 100 57 Example 144 46 759 645 Example 145 2 44 28 Example 146 9 152 67 Example 147 54 982 583 Example 148 62 1037 916 Example 149 5 114 72 Example 150 91 1768 2148 Example 151 122 1641 >4000 Example 152 8 268 132 Example 153 4 74 47 Example 154 10 191 117 Example 155 11 231 141 Example 156 90 885 1006 Example 157 3 84 53 Example 158 5 106 63 Example 159 241 3816 2563 Example 160 15 266 110 Example 161 23 396 169 Example 162 16 290 159 Example 163 N/A* N/A* N/A* Example 164 8 191 121 Example 165 2 47 27 Example 166 13 560 299 Example 167 3 42 33 Example 168 228 3844 >4000 Example 169 46 868 787 Example 170 6 143 89 Example 171 2 33 20 Example 172 95 1632 1072 Example 173 154 2346 1495 Example 174 31 707 429 Example 175 1 20 14 Example 176 33 873 435 Example 177 289 >4000 2911 Example 178 2 52 29 Example 179 46 755 538 Example 180 7 133 78 Example 181 14 260 187 Example 182 10 176 120 Example 183 9 180 125 Example 184 49 991 459 Example 185 67 1545 981 Example 186 6 118 75 Example 187 28 476 321 Example 188 1 23 16 Example 189 183 2973 2414 Example 190 37 623 444 Example 191 0 6 4 Example 192 1 18 11 Example 193 57 939 516 Example 194 4 66 38 Example 195 2 56 34 Example 196 15 354 198 Example 197 11 169 124 Example 198 62 1039 586 Example 199 1 21 15 Example 200 195 3450 3097 Example 201 6 125 74 Example 202 5 94 67 Example 203 3 69 48 Example 204 2 50 29 Example 205 12 331 187 Example 206 27 606 374 Example 207 3 58 39 Example 208 1 32 19 Example 209 33 703 543 Example 210 11 283 162 Example 211 30 618 443 Example 212 84 2366 1111 Example 213 22 529 334 Example 214 2 39 23 Example 215 4 88 57 Example 216 31 743 431 Example 217 39 960 632 Example 218 61 1472 779 Example 219 84 1595 1094 N/A*: Not available. Prodrug of example 75

(141) Test B: Cell Proliferation/Viability Assay on MCF7 (Breast Tumor Cells) WT and Mutants Cell Lines

(142) Test B involves measuring the in vitro proliferation activity of a compound of formula (I) by analyzing the viability of the tumor cells.

(143) The measurements of the viability were made using a breast cancer cell viability assay as described hereunder.

(144) MCF7 cells expressing (and dependent) on mutants estrogen receptor Tyr 537 Ser or Asp 538 Gly were generated by transfection of MCF7 parental cells (ATCC) with expression vectors coding for different mutants of estrogen receptor Tyr 537 Ser or Asp 538 Gly. The cells were first selected by antibiotic (related to vector expression) and then selected for their growth dependence on estrogen receptor based on their ability to grow in vitro in absence of estradiol (parental cell line die in absence of estradiol).

(145) MCF7 cells (ATCC) or MCF7 cells expressing (and dependent) on mutants estrogen receptor Tyr 537 Ser or Asp 538 Gly were seeded in 384 wells microplate at concentration of 1000 cells/30 L per well in red phenol free MEM medium containing 5% charcoal dextran striped FBS. The following day, 9 points serial 1:5 dilution of each compound were added to the cells in 20 L at final concentrations ranging from 3-0.000001 M. After 7 days of compound exposure, 50 L of CellTiter-Glo (Promega) was added to the cells and relative luminescence arbitrary units (RLUs) were determined in luminescence plate reader (Envision device). CellTiter-Glo was added to 50 L medium without cells to determine the background signal.

(146) The percent of viability of each sample was determined as follows: (RLU sampleRLU background/RLU untreatedRLU background)*100=% viability.

(147) The viability activity with respect to estrogen receptors in this test is given by the concentration which inhibits 50% of the viability activity (or IC50) in nM.

(148) The Table 3 below indicates the cell proliferation/viability assay results on MCF7 (breast tumor cells) WT and mutants cell lines, for compounds of formula (I), and demonstrates that the compounds tested have a significant antiproliferative activity regarding estrogen receptors.

(149) TABLE-US-00003 TABLE 3 proliferation proliferation proliferation MCF7 MCF7 MCF7 (WT) D538G Y537S Examples IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) Example 1 0.6 0.1 3 Example 2 1 0.1 6 Example 3 9 0.2 17 Example 4 5 0.2 11 Example 5 0.3 0.2 2 Example 6 3 0.1 3 Example 7 0.2 0.3 1 Example 8 4 0.1 6 Example 9 0.4 1 5 Example 10 7 0.4 15 Example 11 3 0.2 7 Example 12 28 2 35 Example 13 0.5 0.4 5 Example 14 2 0.1 2 Example 15 0.2 0.4 4 Example 16 3 0.4 7 Example 17 0.2 0.3 2 Example 18 0.7 1 5 Example 19 5 0.4 19 Example 20 5 0.1 14 Example 21 23 2 36 Example 22 6 30 306 Example 23 0.2 1 4 Example 24 63 7 71 Example 25 48 5 67 Example 26 25 4 31 Example 27 0.2 1 8 Example 28 0.2 1 7 Example 29 0.5 1 3 Example 30 36 2 39 Example 31 4 0.3 6 Example 32 0.3 1 3 Example 33 0.3 1 3 Example 34 0.2 0.4 2 Example 35 0.2 1 5 Example 36 0.3 0.4 4 Example 37 0.5 1 7 Example 38 0.6 1 9 Example 39 0.2 1 4 Example 40 0.2 0.4 4 Example 41 0.2 1 4 Example 42 0.4 1 6 Example 43 0.4 1 5 Example 44 0.2 1 3 Example 45 0.7 2 14 Example 46 0.6 1 8 Example 47 0.3 0.3 3 Example 48 0.7 2 13 Example 49 0.4 1 5 Example 50 0.2 0.3 4 Example 51 0.4 1 10 Example 52 0.3 1 5 Example 53 10 21 112 Example 54 0.1 0.2 2 Example 55 2 4 39 Example 56 0.5 2 10 Example 57 0.2 0.3 3 Example 58 0.3 1 4 Example 59 0.1 0.5 3 Example 60 0.4 0.3 5 Example 61 0.3 1 4 Example 62 0.4 1 7 Example 63 0.4 1 5 Example 64 0.3 0.4 4 Example 65 0.1 1 2 Example 66 0.4 1 6 Example 67 0.2 0.4 3 Example 68 0.2 0.3 2 Example 69 0.3 1 5 Example 70 0.2 1 8 Example 71 0.2 0.4 4 Example 72 0.6 1 14 Example 73 0.9 2 15 Example 74 0.1 0.3 2 Example 75 0.5 1 7 Example 76 0.2 0.3 3 Example 77 0.1 0.3 2 Example 78 0.4 0.4 6 Example 79 6 0.6 12 Example 80 0.5 1 11 Example 81 0.2 0.2 4 Example 82 0.8 1 8 Example 83 1 1 14 Example 84 0.7 1 13 Example 85 0.8 1 9 Example 86 0.4 1 5 Example 87 0.1 0.4 2 Example 88 0.2 0.3 4 Example 89 0.2 0.3 3 Example 90 0.4 0.3 6 Example 91 0.1 0.2 1 Example 92 0.5 1 8 Example 93 0.2 1 4 Example 94 0.7 1 7 Example 95 0.5 1 10 Example 96 0.8 1 5 Example 97 0.2 0.1 1 Example 98 0.4 0.3 2 Example 99 0.4 1 3 Example 100 1 2 15 Example 101 0.8 1 6 Example 102 0.1 0.3 1 Example 103 0.5 1 5 Example 104 0.1 0.1 1 Example 105 0.3 0.3 4 Example 106 1 3 54 Example 107 0.5 1 12 Example 108 0.2 0.1 1 Example 109 0.2 0.1 2 Example 110 0.4 1 9 Example 111 0.2 0.2 3 Example 112 0.2 0.2 4 Example 113 0.6 2 11 Example 114 0.4 1 5 Example 115 0.3 1 5 Example 116 0.1 1 2 Example 117 0.5 1 6 Example 118 0.2 0.2 2 Example 119 0.7 2 8 Example 120 0.3 1 6 Example 121 0.3 1 2 Example 122 0.2 1 2 Example 123 0.2 1 5 Example 124 0.3 1 4 Example 125 0.2 1 3 Example 126 1 3 30 Example 127 0.1 0.4 1 Example 128 8 17 96 Example 129 0.1 0.3 5 Example 130 0.2 1 5 Example 131 0.4 1 11 Example 132 0.7 2 19 Example 133 1 2 29 Example 134 0.1 0.3 3 Example 135 1 3 21 Example 136 0.2 1 5 Example 137 0.2 1 7 Example 138 0.8 3 19 Example 139 0.1 1 3 Example 140 1 3 24 Example 141 0.3 1 5 Example 142 0.2 0.2 2 Example 143 0.7 1 5 Example 144 2 2 25 Example 145 0.3 0.4 3 Example 146 0.4 1 4 Example 147 2 2 20 Example 148 2 2 11 Example 149 0.7 1 6 Example 150 3 2 18 Example 151 0.9 1 16 Example 152 0.4 0.3 4 Example 153 0.1 0.1 1 Example 154 0.4 0.3 4 Example 155 0.1 0.2 2 Example 156 2 4 11 Example 157 0.6 0.2 2 Example 158 0.5 1 5 Example 159 8 11 112 Example 160 0.7 1 6 Example 161 0.8 1 7 Example 162 0.6 1 3 Example 163 N/A* N/A* N/A* Example 164 2 0.2 2 Example 165 0.4 0.3 4 Example 166 0.8 1 12 Example 167 0.4 1 3 Example 168 4 5 33 Example 169 10 1 1 Example 170 3 0.3 0.3 Example 171 0.9 0.1 0.1 Example 172 30 2 4 Example 173 5 11 177 Example 174 1 3 40 Example 175 0.2 1 10 Example 176 5 12 108 Example 177 11 18 187 Example 178 0.5 2 15 Example 179 1 3 35 Example 180 2 3 39 Example 181 2 4 52 Example 182 0.3 1 15 Example 183 1 1 9 Example 184 1 2 36 Example 185 41 77 1000 Example 186 0.9 2 26 Example 187 19 34 1000 Example 188 0.1 0.1 3 Example 189 12 27 246 Example 190 7 15 148 Example 191 0.5 2 19 Example 192 0.6 2 17 Example 193 0.6 1 20 Example 194 0.3 1 8 Example 195 0.2 0.2 4 Example 196 1 5 43 Example 197 0.2 1 6 Example 198 3 11 79 Example 199 0.2 1 2 Example 200 78 108 1000 Example 201 0.02 1 4 Example 202 0.3 1 6 Example 203 0.1 1 4 Example 204 0.1 0.3 1 Example 205 8 28 119 Example 206 1 8 26 Example 207 0.3 1 3 Example 208 0.1 0.3 1 Example 209 8 25 68 Example 210 0.5 2 8 Example 211 0.7 2 10 Example 212 4 14 112 Example 213 1 2 8 Example 214 0.1 1 2 Example 215 1 18 51 Example 216 1 6 19 Example 217 0.3 12 23 Example 218 1 13 29 Example 219 1 9 36 N/A*: Not available. Prodrug of example 75

(150) Test C: Estrogen Receptor Degradation Activity

(151) Test C involves measuring the in vitro degradation activity of a compound of formula (I).

(152) The measurements of the degradation activities were made using a breast cancer cell ER in cell western assay as described hereunder.

(153) MCF7 cells (ATCC) were seeded in 384 wells microplate (collagen coated) at concentration of 10000 cells/30 L per well in red phenol free MEM alpha medium (Invitrogen) containing 5% charcoal dextran striped FBS. The following day, 9 points serial 1:5 dilution of each compound were added to the cells in 2.5 L at final concentrations ranging from 3-0.000018 M or 0.1 M for fulvestrant (using as positive control). At 4 hours post compounds addition the cells were fixed by adding 25 L of formalin (final concentration 5% formalin containing 0.1% triton) for 10 minutes at room temperature and then washed twice with PBS. Then, 50 L of LI-COR blocking buffer containing 0.1% Triton was added to plate for 30 minutes at room temperature. LI-COR blocking buffer was removed and cells were incubated overnight at cold room with 50 L anti-ER rabbit monoclonal antibody (Thermo scientific MAI-39540) diluted at 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells which were treated with blocking but no antibody were used as background control. Wells were washed twice with PBS (0.1% tween-20) and incubated at 37 C. for 60 minutes in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 M final concentration). Cells were then washed 3 times in PBS and scanned in ACUMEN explorer (TTP-Labtech). Integrated intensities in the green fluorescence and red fluorescence were measured to determine the levels of ER and DNA respectively.

(154) The degradation activity with respect to estrogen receptors in this test is given by the concentration which degrades 50% of the estrogen receptor (or IC50) in nM.

(155) The % of ER levels decrease were determined as follows: % inhibition=100*(1-(samplefulvestrant:DMSOfulvestrant)).

(156) The Table 4 below indicates the estrogen receptor degradation activity results for compounds of formula (I), and demonstrates that compounds tested have a significant degradation activity on estrogen receptors.

(157) TABLE-US-00004 TABLE 4 Degradation % Degradation Examples IC.sub.50 (nM) At 3 M Example 1 0.4 88 Example 2 0.4 97 Example 3 3 82 Example 4 0.3 90 Example 5 0.3 93 Example 6 0.7 90 Example 7 0.5 97 Example 8 0.5 96 Example 9 0.7 95 Example 10 0.2 92 Example 11 0.7 89 Example 12 0.5 82 Example 13 0.5 91 Example 14 0.3 94 Example 15 0.2 95 Example 16 2 90 Example 17 0.8 83 Example 18 0.9 90 Example 19 1 82 Example 20 0.2 87 Example 21 0.2 83 Example 22 2 81 Example 23 2 82 Example 24 28 86 Example 25 38 91 Example 26 11 92 Example 27 2 91 Example 28 1 92 Example 29 0.4 88 Example 30 2 82 Example 31 1 91 Example 32 2 87 Example 33 0.6 86 Example 34 1 83 Example 35 0.8 89 Example 36 0.4 90 Example 37 1 95 Example 38 1 96 Example 39 0.5 91 Example 40 0.2 88 Example 41 0.3 85 Example 42 0.3 84 Example 43 0.2 83 Example 44 0.2 80 Example 45 0.2 93 Example 46 0.2 94 Example 47 0.4 90 Example 48 0.2 96 Example 49 0.2 94 Example 50 0.4 92 Example 51 0.2 98 Example 52 0.4 92 Example 53 8 95 Example 54 0.2 92 Example 55 5 87 Example 56 2 85 Example 57 0.5 86 Example 58 0.7 84 Example 59 0.4 86 Example 60 1 84 Example 61 1 86 Example 62 0.7 96 Example 63 0.3 95 Example 64 0.4 88 Example 65 0.8 89 Example 66 0.6 90 Example 67 2 92 Example 68 1 92 Example 69 0.2 87 Example 70 0.7 80 Example 71 0.6 83 Example 72 2 88 Example 73 0.4 86 Example 74 0.4 84 Example 75 2 84 Example 76 0.3 88 Example 77 0.3 83 Example 78 0.9 92 Example 79 0.9 84 Example 80 1 90 Example 81 0.6 83 Example 82 0.5 83 Example 83 2 80 Example 84 2 92 Example 85 1 92 Example 86 0.7 89 Example 87 0.4 90 Example 88 0.5 86 Example 89 0.6 84 Example 90 1 83 Example 91 0.2 86 Example 92 2 89 Example 93 0.3 86 Example 94 2 88 Example 95 1 84 Example 96 1 86 Example 97 0.7 95 Example 98 1 86 Example 99 0.9 94 Example 100 3 93 Example 101 1 87 Example 102 0.6 87 Example 103 1 86 Example 104 0.6 84 Example 105 0.3 93 Example 106 2 87 Example 107 2 89 Example 108 0.2 87 Example 109 0.5 80 Example 110 0.8 83 Example 111 0.3 84 Example 112 0.6 88 Example 113 0.2 90 Example 114 0.2 88 Example 115 0.2 89 Example 116 0.2 85 Example 117 0.2 85 Example 118 0.2 87 Example 119 0.2 81 Example 120 0.2 85 Example 121 0.2 87 Example 122 0.2 85 Example 123 0.2 83 Example 124 0.2 87 Example 125 0.2 93 Example 126 0.2 86 Example 127 0.2 89 Example 128 1 82 Example 129 0.2 90 Example 130 0.2 80 Example 131 0.2 84 Example 132 0.3 89 Example 133 0.2 88 Example 134 0.2 87 Example 135 0.2 85 Example 136 0.2 82 Example 137 0.2 85 Example 138 0.3 88 Example 139 0.2 80 Example 140 0.2 86 Example 141 0.2 84 Example 142 0.2 84 Example 143 0.2 81 Example 144 2 86 Example 145 0.2 83 Example 146 0.2 83 Example 147 0.2 88 Example 148 0.2 83 Example 149 0.2 82 Example 150 1 82 Example 151 1 81 Example 152 0.2 80 Example 153 0.2 91 Example 154 0.2 87 Example 155 0.2 89 Example 156 0.2 85 Example 157 0.2 81 Example 158 0.2 82 Example 159 0.7 84 Example 160 0.2 83 Example 161 0.2 81 Example 162 0.2 82 Example 163 N/A* N/A* Example 164 0.2 88 Example 165 0.2 82 Example 166 0.5 86 Example 167 0.2 81 Example 168 0.6 91 Example 169 1 87 Example 170 0.5 82 Example 171 0.3 83 Example 172 2 80 Example 173 9 85 Example 174 0.7 92 Example 175 0.2 88 Example 176 2 81 Example 177 8 92 Example 178 0.2 94 Example 179 0.9 94 Example 180 3 91 Example 181 3 94 Example 182 0.2 93 Example 183 0.7 98 Example 184 2 95 Example 185 9 80 Example 186 0.9 87 Example 187 15 90 Example 188 0.2 91 Example 189 22 90 Example 190 7 80 Example 191 0.5 89 Example 192 0.3 88 Example 193 0.2 88 Example 194 0.8 90 Example 195 0.2 87 Example 196 8 86 Example 197 0.6 92 Example 198 3 81 Example 199 0.2 95 Example 200 15 85 Example 201 0.3 90 Example 202 0.2 84 Example 203 0.2 81 Example 204 0.2 82 Example 205 4 88 Example 206 1 85 Example 207 0.2 86 Example 208 0.2 94 Example 209 8 91 Example 210 1 91 Example 211 0.3 95 Example 212 2 94 Example 213 0.2 96 Example 214 0.5 92 Example 215 1.5 80 Example 216 3 90 Example 217 2 90 Example 218 3 92 Example 219 1 89 N/A*: Not available. Prodrug of example 75

(158) It is therefore apparent that the compounds of formula (I), or a pharmaceutically acceptable salt thereof, have antagonist and degradation activities for estrogen receptors, as well as antiproliferative activity. The compounds of formula (I), or a pharmaceutically acceptable salt thereof, can therefore be used for preparing medicaments, especially medicaments which are antagonists and degraders of estrogen receptors.

(159) Accordingly, also provided are medicaments which comprise a compound of the formula (I), or a pharmaceutically acceptable salt thereof.

(160) Another aspect is the compounds of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in therapy, especially as inhibitors and degraders of estrogen receptors.

(161) Another aspect is the compounds of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

(162) A particular aspect are the compounds of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

(163) In an embodiment, the cancer is a hormone dependent cancer.

(164) In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor a dependent cancer.

(165) In another embodiment, the cancer is a cancer with wild type estrogen receptors.

(166) In another embodiment, the cancer is a cancer with deregulated function of estrogen receptors related to, but not limited to, at least one epigenetic and genetic alteration of estrogen receptors such us mutation, amplification, splice variant.

(167) In another embodiment, the cancer is a cancer with mutated estrogen receptors.

(168) In another embodiment, the mutations of estrogen receptors can include, but not limited to, new or known mutations such us Leu536Arg, Tyr537Ser, Tyr537Asn, Asp538Gly.

(169) In another embodiment, the cancer is an estrogen-sensitive cancer.

(170) In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.

(171) In another embodiment, the metastasis is a cerebral metastasis.

(172) In another embodiment, the cancer is breast cancer. Particularly, the breast cancer is an estrogen receptor positive breast cancer (ER positive breast cancer).

(173) In another embodiment, the cancer is resistant to anti-hormonal treatment.

(174) In a further embodiment, the anti-hormonal treatment is as single agent or in combination with other agents such as CDK4/6 or PI3K inhibitors.

(175) In a further embodiment, the anti-hormonal treatment includes treatment with at least one agent selected from tamoxifen, fulvestrant, a steroidal aromatase inhibitor, and a non-steroidal aromatase inhibitor.

(176) Another embodiment is a method of treating the pathological conditions indicated above, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment of this method of treatment, the subject is a human.

(177) Another aspect is the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating any of the pathological conditions indicated above, more particularly the use in treating cancer.

(178) Another aspect is a pharmaceutical composition comprising as active principle a compound of formula (I) or a pharmaceutically acceptable salt thereof. These pharmaceutical compositions comprise an effective dose of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

(179) The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

(180) In the pharmaceutical compositions provided herein for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intra-tracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or its base, acid, zwitterion or salt thereof, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals and to human beings for the treatment of the above disorders or diseases.

(181) The unit administration forms appropriate include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intra-tracheal, intra-ocular and intra-nasal administration forms, forms for inhalative, topical, transdermal, subcutaneous, intra-muscular or intravenous administration, rectal administration forms and implants. For topical application it is possible to use the compounds of formula (I), or a pharmaceutically acceptable salt thereof, in creams, gels, ointments or lotions.

(182) As an example, a unit administration form of a compound of formula (I) in tablet form may comprise the following components:

(183) TABLE-US-00005 Compound of formula (I) 50.0 mg Mannitol 223.75 mg Sodium croscarmellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

(184) There may be particular cases in which higher or lower dosages are appropriate. According to usual practice, the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.